Logout
 CME Information
 Editorial Board
 Lessons by Volume
   Volume 22
   Volume 21
   Volume 20
   Volume 19
   Volume 18
   Volume 17
   Volume 16
   Volume 15
 
 

Lesson 15, Volume 15—Antibiotic Resistance in Community-Acquired Pneumonia

By Ronald Grossman, MD, FCCP

Effective December 31, 2004, PCCU Volume 15 is available for review purposes only. CME credit for this volume is no longer being offered.

Objectives

  1. To identify the major respiratory pathogens in patients with community-acquired pneumonia by site of care.
  2. To appreciate the current levels of antimicrobial resistance globally.
  3. To understand the mechanisms of resistance.
  4. To appreciate the clinical relevance of antimicrobial resistance.

Key words

community-acquired pneumonia; b-lactamase-producing Haemophilus influenzae; b-lactamase-producing Moraxella catarrhalis; penicillin-resistant Streptococcus pneumoniae

Abbreviations

CAP = community-acquired pneumonia; MIC90 = minimum inhibitory concentration; PNSP = penicillin-nonsusceptible pneumococci

Community-acquired pneumonia (CAP) is a common illness, affecting approximately 4 million adults in the United States annually. Roughly 15% (600,000) of these patients are hospitalized.1 Because the microbial etiology of CAP varies according to the severity of illness, several recently published guidelines for the management of patients with CAP have adopted site-specific recommendations for treatment.2,3 The simplest approach is to group patients based on the physician's decision regarding the patient's need for hospitalization and/or ICU care. This can be simplified to include (1) outpatients; (2) inpatients, hospital ward; (3) inpatients, ICU; and (4) nursing home.

Etiology

Etiology of Pneumonia Treated in an Outpatient Setting

Although as many as 80% of patients with pneumonia are treated on an ambulatory basis, the etiology of pneumonia in this group of patients has not been well studied. Mycoplasma pneumoniae is more common in ambulatory patients than in those patients requiring hospital admission and is thought to be the most common cause of pneumonia in this setting.4 However, in many of the studies examining etiology in this setting, the importance of bacterial pathogens is understated because sputum specimens were not collected from many of the outpatients and, even when collected, technical difficulties precluded in-depth analysis.

Etiology of CAP Requiring Admission to Hospital

The most frequent etiologic agent of CAP in patients requiring hospitalization is Streptococcus pneumoniae, with a frequency ranging from 5 to 55%.5,6 Using various methods to detect antibodies to pneumolysin, techniques that greatly increase the yield of pneumococcal infection, about half of all cases of CAP can be attributed to S pneumoniae. The reliability of these techniques, however, has been questioned. A declining incidence of pneumococcal infection has been recently found.7 Antibiotic therapy administered just before the collection of a sputum sample probably accounts for this observation but lack of bedside inoculation of sputum for culture (done in earlier studies, but not done now) and other factors may also be important.

Chlamydia pneumoniae is recognized as the second most common cause of pneumonia, with a range of 3.4 to 43% in various studies.6,7 The third most common cause of CAP requiring hospitalization is Haemophilus influenzae. Most studies have shown a higher prevalence of H influenzae pneumonia in patients with COPD, although in a recent study targeting patients with COPD and pneumonia, H influenzae was the third ranked agent, accounting for 9% of the cases.8

Legionella pneumophila accounts for 2 to 6% of cases of CAP requiring hospitalization and is very geographic-dependent. About one half of these cases are related to L pneumophila serogroup 1 while Legionella micdadei, Legionella feelii, Legionella bozemanii, Legionella dumoffii, and Legionella longbeachae account for slightly more than 10% of cases.9

Aerobic Gram-negative rods including Escherichia coli, Klebsiella spp, etc., are uncommon causes of CAP overall. Risk factors for the isolation of these organisms include:

  • critical illness requiring ICU admission;
  • severe structural lung disease;
  • recent administration of broad-spectrum antimicrobials; and
  • chronic oral corticosteroid therapy.

M pneumoniae can occasionally cause severe pneumonia, even to the extent that ventilatory assistance is required. Infection with respiratory tract viruses often precedes pneumonia and may be important in the pathogenesis of pneumonia in those patients requiring hospitalization. Respiratory syncytial virus, a well-known pathogen in children, is emerging as an important respiratory pathogen in adults. Mycobacterium tuberculosis accounts for 1.4 to 10% of cases of CAP requiring hospitalization. Pneumocystis carinii caused 2% of CAP requiring admission to hospital early in the HIV epidemic but is much less common now.10

Patients prone to aspiration during episodes of decreased consciousness (seizures, neurologic diseases affecting the swallowing mechanism, drug overdose, alcohol, etc.) may be infected with anaerobes.11 The risk of pleuropulmonary anaerobic infection is increased in the presence of periodontal disease or dental caries (which increase the inoculum of anaerobes aspirated).12 Pulmonary infection with anaerobes are usually associated with foul-smelling sputum, lung abscess, and empyema.13

Despite extensive investigation there is always a subset of patients with pneumonia of unknown etiology. It is likely that some of these cases of unknown etiology are caused by undiscovered pathogens.

Etiology of Nursing Home–Acquired Pneumonia

In virtually every study of pneumonia in the aged, S pneumoniae is the most commonly isolated pathogen. The rate of colonization of the oropharynx by Gram-negative rods rises with increasing age.14 The relevance of this observation is not entirely clear. Because macroaspiration is common in nursing home patients, it is possible that Gram-negative rods are important in nursing home-acquired pneumonia. Reliance on sputum culture to make an etiologic diagnosis is a major limitation of studies of nursing home-acquired pneumonia. In some studies, aerobic Gram-negative rods rates as high as 40% have been identified, which runs contrary to most other studies.15

Severe CAP

S pneumoniae is the most commonly isolated causative organism in patients treated in the ICU, identified in 17 to 34% of cases.16,17 The other common bacterial pathogens are L pneumophila, H influenzae, and Staphylococcus aureus. However, any agent that causes pneumonia can result in infection severe enough to require intensive care. Both aerobic Gram-negative bacilli and Legionella occur more frequently in patients treated in the intensive care setting than in those treated elsewhere.

Although a causative organism is more commonly identified in CAP patients treated in an ICU than elsewhere, an etiologic agent is only identified in approximately 60% of the patients despite the more intensive diagnostic testing.

Penicillin Resistance in S pneumoniae

Definition

A minimum inhibitory concentration (MIC90) of < 0.1 mg/L defines penicillin-susceptible S pneumoniae.18 Intermediate penicillin resistance is defined by an MIC90 of 0.1 to 1.0 mg/L, while high-level penicillin resistance is defined by an MIC90 > 2.0 mg/L. S pneumoniae with reduced susceptibility to penicillin is often referred to as penicillin-nonsusceptible pneumococci (PNSP; MIC90 > 0.1 mg/L) or penicillin-resistant pneumococci (MIC90 > 2.0 mg/L). Resistance to two or more classes of antimicrobials with different mechanisms of action defines multidrug-resistant S pneumoniae.19

The first reported case of clinically significant infection caused by a penicillin-resistant strain of S pneumoniae was in Australia in 1967.20 Since then, the isolation of PNSP has been reported worldwide but with wide variation from country to country for reasons that are not well understood. Regional differences in patterns of antibiotic use, including dosing regimens, compliance issues, and cost, explain some but not all of this variability.

Prevalence of Drug-Resistant S pneumoniae

In the United States, the prevalence of PNSP increased from 5% in 1987 to 8% by 1992, and 25% by 1995 (7 to 10% penicillin-resistant pneumococci).21-23 A national survey during 1997 found that among 845 clinical isolates of S pneumoniae from 34 different medical centers, 27.8% (range, 10.5 to 50.0%) had intermediate penicillin susceptibility, while 16% (range, 0 to 36.8%) were highly resistant to penicillin.24 Another survey involving 4,152 isolates collected from 163 US institutions from December 1997 to May 1998 indicated that 22.0% demonstrated intermediate penicillin susceptibility, while 13.0% of strains had high-level resistance.25 More recently, 4,013 cases of invasive S pneumoniae disease were reported; 24% were resistant to penicillin, but in some states (Tennessee and Georgia), the rate was as high as 35%.26

High-level resistance to penicillin in S pneumoniae is related to altered b-lactam target sites (penicillin-binding proteins), and, in contrast to the penicillin resistance in H influenzae and M catarrhalis due to b-lactamase production, cannot be overcome by the addition of a b-lactamase inhibitor. There are six penicillin-binding proteins and, among strains that have high-level resistance to penicillin, reduction in the affinity of at least three penicillin-binding proteins has been found. Penicillin resistance in S pneumoniae is often a marker for a multidrug-resistant phenotype.27 These strains frequently demonstrate reduced susceptibility to oral cephalosporins, macrolides, trimethoprim-sulfamethoxazole, and tetracyclines. Vancomycin and the "respiratory" fluoroquinolones (eg, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin and trovafloxacin) are the only antibiotics equally active against both penicillin-susceptible and penicillin-resistant strains of S pneumoniae.27-29

Risk Factors for Drug-Resistant S pneumoniae

While the overall percentage of strains demonstrating reduced susceptibility to penicillin is increasing throughout the United States and Canada, there are regional discrepancies and certain patient groups appear to be more likely to be infected with these strains.30,31 The following have been determined to be risk factors for infection with drug-resistant S pneumoniae:

  • age < 6 years or > 70 years;
  • recent antimicrobial therapy;
  • immunosuppression, HIV disease;
  • coexisting illness or underlying disease;
  • recent or current hospitalization;
  • institutionalization;
  • member of the military; and
  • family member of or child attending day care

Are Penicillin-Resistant Strains Less Pathogenic than Penicillin-Sensitive Strains?

Two studies have reported a lower rate of bacteremia associated with penicillin-resistant S pneumoniae infections compared with penicillin-susceptible S pneumoniae infections (8 vs 29%) suggesting that these strains may be less virulent.32,33 Failure of penicillin therapy has been documented for meningitis and otitis media, but not for nonmeningeal infections with penicillin-resistant S pneumoniae.33-35 Some comparative studies of adults and children have indicated that infection with penicillin-nonsusceptible strains has not influenced the outcome of pneumonia.36,37 Other studies and recent case reports indicate that penicillin resistance may have an impact on mortality.38-41 In particular, Feiken and associates38 suggested that mortality was increased among patients with pneumococcal isolates with an MIC90 > 4 mg/L, but only after the first 4 days of hospitalization were excluded.38 The authors reasoned that early deaths are not affected by antimicrobial therapy and only deaths occurring after 4 days of hospitalization could be attributed to antimicrobial failure. This was originally pointed out by Austrian and Gold42 decades ago, when they showed a reduction in pneumococcal pneumonia mortality related to penicillin administration only after the fifth day of illness. The major shortcoming of this study is that the antibiotics used are not identified so that intrinsic antimicrobial activity and outcome cannot be linked. While there is conflicting clinical evidence regarding the importance of penicillin resistance particularly for MIC90 values ranging from 1 to 4 mg/mL, most investigators anticipate clinical failures when the MIC90 exceeds 4 mg/mL.

Treatment for PNSP Strains

Most strains, even those with high-level resistance, have MIC90 values of 4 mg/L or lower.24,28 Pharmacokinetic and dynamic considerations imply that b-lactams would be effective against strains demonstrating MIC90 levels < 2 mg/L. The peak serum concentration of penicillin G administered IV at 40,000 U/kg q4h is approximately 40 mg/L, and after oral administration of amoxicillin 500 mg, the peak concentration ranges from 5.5 to 11.0 mg/L. In most instances, this would lead to a serum concentration higher than the MIC90 for more than 40% of the dosing interval (a value that experimentally is required for excellent bacterial killing and good clinical outcomes).43 Thus, the current laboratory definitions of penicillin resistance for noncerebrospinal-fluid isolates of S pneumoniae may not be clinically relevant. For intermediately resistant strains, either amoxicillin (500 mg tid) or cefuroxime (500 mg bid) remains effective as oral therapy.29 For highly resistant strains with MIC _ 2 mg/L, high-dose IV penicillin (2 MU q6h) is still effective. Respiratory fluoroquinolones or parenteral treatment with a third-generation cephalosporin (eg, cefotaxime 1 g q8h or ceftriaxone 1 g q24h) are alternative choices.

Macrolide Resistance in S pneumoniae

Macrolide resistance in S pneumoniae occurs in 23% of isolates in the United States and > 11% of strains in Canada.29 Target site modification mediated by one or more methylase genes (erm), or by an efflux pump mechanism mediated by the mef gene are the major mechanisms of resistance.29 The rise in MIC to macrolides tends to be abrupt and of greater magnitude (MIC90 >10 mg/L) than that seen with penicillin resistance in S pneumoniae, where the increase in MIC to penicillin is incremental over time. Furthermore, among intermediately penicillin-resistant strains in the United States, approximately 40% of strains are resistant to azithromycin and clarithromycin and > 65% are resistant when high-level resistant strains are isolated.25 Despite this, very few cases have been reported in which the presence of macrolide resistance in vitro in patients with S pneumoniae pneumonia has led to clinical failure or break-through bacteremia during macrolide therapy.44,45 This is in part due to the fact that the etiology of CAP is not identified in > 50% of cases, and any association of treatment failure with macrolide-resistant S pneumoniae may be difficult to detect or confirm clinically. Another possible explanation is that because macrolides are highly concentrated in alveolar macrophages, achieving concentrations that are several-fold higher than those available in serum, in vitro susceptibility results may not accurately predict in vivo activity.46 There is considerable evidence that macrolides are highly effective as monotherapy for outpatients with mild to moderate CAP.47,48 There is equally compelling evidence of the efficacy of macrolides added to a parenteral cephalosporin in the management of patients with pneumonia who are ill enough to require hospitalization.

Fluoroquinolone Resistance in S pneumoniae

Matsumura and coworkers49 found no increase in fluoroquinolone resistance between 1988 and 1995 in a cross-Canada survey of S pneumoniae susceptibility. There has been an increase in fluoroquinolone resistance among S pneumoniae in Canada, from 0% in 1993 to 1.7% during 1997 and 1998.50 The prevalence of fluoroquinolone resistance was higher in isolates from older patients (2.6% among those > 65 years of age vs 1.0% among those 15 to 64 years of age; p < 0.001), and among those from Ontario (1.5% vs 0.4% among those from the rest of Canada; p < 0.001). Wise et al51 also found two of 29 clinical isolates to be highly resistant to ciprofloxacin and even demonstrated reduced susceptibility to newer fluoroquinolones with enhanced Gram-positive activity. For reasons that are not entirely clear, this observation has not been repeated in the United States.25 The mechanism of fluoroquinolone resistance is mediated either by mutations in the target topoisomerases (gyrA and/or parC), or by an efflux pump mechanism.29

b-Lactamase Production in H influenzae and M catarrhalis

Aminopenicillin resistance due to b-lactamase production by H influenzae currently exceeds 30% in the US.52 Nearly all strains are susceptible to ceftriaxone and cefuroxime. b-Lactamase-producing strains of H influenzae demonstrate reduced susceptibility to the macrolides, but the clinical relevance of this observation is questionable.22 While the fluoroquinolones have better H influenzae eradication rates than macrolides in patients with acute exacerbations of chronic bronchitis, the clinical outcomes are usually similar.53 Aminopenicillin resistance in M catarrhalis is stable at approximately 90%, but second- or third-generation cephalosporins and amoxicillin/clavulanate remain active against these organisms.54

Empiric Therapy Regimens

The recently published guidelines from Canada and the Infectious Diseases Society of America are remarkably similar in their recommendations for the management of patients with CAP.2,3 For outpatients with no specific risk factors for drug-resistant S pneumoniae or Gram-negative organisms, either a macrolide or tetracycline is recommended. The Canadians recommend a respiratory fluoroquinolone only for patients suspected of having infection caused by Gram-negative organisms (structural lung disease, recent antibiotics within 3 months, chronic oral corticosteroids administration) whereas the Infectious Diseases Society of America suggests a fluoroquinolone as an option for all outpatients. The implication is that the Canadians are not as concerned about the role of resistance in clinical outcomes mainly because resistance rates in Canada are lower than in the United States and clinical failures related to resistance are extremely hard to find. This is true for Canada and the United States. Both guidelines agree that a respiratory fluoroquinolone is an appropriate first choice for patients admitted to the hospital ward. The alternative choice would be a combination of a macrolide plus a second-, third-, or fourth-generation cephalosporin. The rationale for these choices involves appropriate coverage of the likely pathogens, improved clinical outcomes, and the concern of pneumococcal resistance.55 For patients with life-threatening illness requiring ICU admission but no suspicion of Pseudomonas aeruginosa infection, a combination of a respiratory fluoroquinolone plus an advanced-generation cephalosporin or b-lactam/b-lactamase inhibitor or a macrolide plus a similar b-lactam choice is appropriate. For patients suspected of being infected with P aeruginosa, an antipseudomonal fluoroquinolone is substituted for a respiratory fluoroquinolone and an antipseudomonal b-lactam (ceftazidime, piperacillin-tazobactam, imipenem, meropenem) is necessary.

Conclusion

Increasing rates of antimicrobial resistance of the major respiratory pathogens, S pneumoniae, H influenza, and M catarrhalis to first-line agents such as b-lactams and macrolides are forcing physicians to consider alternative therapies. Careful application of guidelines and reduced antibiotic prescribing for nonbacterial infections such as otitis media and viral tracheobronchitis should permit the use of standard medications for some time to come. There will be a need to develop new classes of antimicrobials as resistance rates worsen. Complacency may lead to a situation where patients with CAP may not be treatable with antibiotics.

References

  1. Gilbert K, Fine MJ. Assessing prognosis and predicting patient outcomes in community-acquired pneumonia. Semin Respir Infect 1994; 9:140-15
  2. Mandell LA, Marrie TJ, Grossman RF, et al. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000; 31:383-421
  3. Bartlett JG, Dowell SF, Mandell LA, et al. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000; 31:347-382
  4. Marrie TJ, Peeling RW, Fine MJ, et al. Ambulatory patients with community-acquired pneumonia: the frequency of atypical agents and clinical course. Am J Med 1996; 101:508-515
  5. Levy M. Community-acquired pneumonia: importance of initial noninvasive bacteriologic and radiographic investigations. Chest 1988; 92:43-48
  6. Kauppinen MT, Herva E, Kujala P, et al. The etiology of community-acquired pneumonia among hospitalized patients during a Chlamydia pneumoniae epidemic in Finland. J Infect Dis 1995; 172:1330-1335
  7. Mundy LM, Auwaerter PG, Oldach D, et al. Community-acquired pneumonia: impact of immune status. Am J Respir Crit Care Med 1995; 152:1309-1315
  8. Torres A, Dorca J, Zalacain R, et al. Community-acquired pneumonia in chronic obstructive pulmonary disease: a Spanish multicenter study. Am J Respir Crit Care Med 1996; 154:1456-1461
  9. Marston BJ, Plouffe JF, File TM Jr, et al. Incidence of community-acquired pneumonia requiring hospitalization: results of a population-based active surveillance study in Ohio. Arch Intern Med 1997; 157:1709-1718
  10. Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis 1989; 11:586-599
  11. Bartlett JG, Finegold SM. Anaerobic pleuropulmonary infections. Medicine (Baltimore) 1972; 51:413-450
  12. Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest 1975; 68:560-566
  13. Bartlett JG, Finegold SM. Anaerobic infections of the lung and pleural space. Am Rev Respir Dis 1974; 110:56-77
  14. Valenti WM, Trudell RG, Bentley DW. Factors predisposing to oropharyngeal colonization with gram-negative bacilli in the aged. N Engl J Med 1978; 298:1108-1111
  15. Garb JL, Brown RB, Garb JR, et al. Differences in etiology of pneumonias in nursing home and community patients. JAMA 1978; 240:2169-2172
  16. Leroy O, Santre C, Beuscart C. A 5-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an ICU. Intensive Care Med 1995; 21:24-31
  17. Olaechea PM, Quintana JM, Gallardo MS, et al. A predictive model for the treatment approach to community-acquired pneumonia in patients needing ICU admission. Intensive Care Med 1996; 22:1294-1300
  18. Performance standards for antimicrobial susceptibility testing. Villanova, PA: National Committee for Clinical Laboratory Standards, 1997
  19. Hofmann J, Cetron MS, Farley MM, et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995; 333:481-486
  20. Appelbaum PC. World-wide development of antibiotic resistance in pneumococci. Eur J Clin Microbiol 1987; 6:367-377
  21. Butler JC, Hofmann J, Cetron MS, et al. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System. J Infect Dis 1996; 174:986-993
  22. Thornsberry C, Ogilvie P, Kahn J, et al. Surveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States in 1996-1997 respiratory season. Diagn Microbiol Infect Dis 1997; 29:249-257
  23. Doern GV. Trends in antimicrobial susceptibility of bacterial pathogens of the respiratory tract. Am J Med 1995; 99(suppl 6B):3S-7S
  24. Doern GV, Pfaller MA, Kugler K, et al. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from the SENTRY Antimicrobial Surveillance Program. Clin Infect Dis 1998; 27:764-770
  25. Thornsberry C, Hickey ML, Kahn J, et al. Surveillance of antimicrobial resistance among respiratory tract pathogens in the United States, 1997 to 1998. Drugs 1999; 58(suppl 2):361-363
  26. Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000; 343:1917-1924
  27. Murray BE. The growing threat of penicillin-resistant Streptococcus pneumoniae. Infect Dis Clin Pract 1997; 6 (suppl 2):S21-S27
  28. Zhanel GG, Karlowsky JA, Palatnick L, et al. Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study. Antimicrob Agents Chemother 1999; 43:2504-2509
  29. Low DE. Resistance issues and treatment implications: Pneumococcus, Staphylococcus aureus and gram negative rods. Infect Dis Clin North Am 1998; 12:613-630
  30. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990; 3:171-196
  31. Nava JM, Bella F, Garau J, et al. Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae: a population based study. Clin Infect Dis 1994; 19:884-890
  32. Einarsson S, Kristjansson M, Kristinsson KG, et al. Pneumonia caused by penicillin-non-susceptible and penicillin-susceptible pneumococci in adults: a case-control study. Scand J Infect Dis 1998; 30:253-256
  33. Ewig S, Ruiz M, Torres A, et al. Pneumonia acquired in the community through drug-resistant Streptococcus pneumoniae. Am J Respir Crit Care Med 1999; 159:1835-1842
  34. Shafran SD. Antibiotics for community-acquired respiratory tract infections: are the benefits worth the risks? Can J Infect Dis 1998; 9:202-204
  35. Klugman KP, Feldman C. The clinical relevance of antibiotic resistance in the management of pneumococcal pneumonia. Infect Dis Clin Pract 1998; 7:180-184
  36. Pallares R, Linares J, Vadillo M, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain [published erratum appears in N Engl J Med 1995; 333(24):1655]. N Engl J Med 1995; 333:474-480
  37. Friedland IR. Comparison of the response to antimicrobial therapy of penicillin-resistant and penicillin-susceptible pneumococcal disease. Pediatr Infect Dis J 1995; 14:885-890
  38. Feikin DR, Schuchat A, Kolczak M, et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. Am J Public Health 2000; 90:223-229
  39. Turret GS, Blum S, Fazal BA, et al. Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high HIV seroprevalence. Clin Infect Dis 1999; 29:321-327
  40. Buckingham SC, Brown SP, Joaquin VH. Breakthrough bacteremia and meningitis during treatment parenterally with cephalosporins for pneumococcal pneumonia. J Pediatr 1998; 132:174-176
  41. Dowell SF, Smith T, Leversedge K, et al. Pneumonia treatment failure associated with highly resistant pneumococci. Clin Infect Dis 1999; 29:462-463
  42. Austrian R, Gold J. Pneumococcal bacteremia with special reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964; 60:759-776
  43. Craig W. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1-12
  44. Moreno S, Garcia-Leoni ME, Cercenado E, et al. Infections caused by erythromycin-resistant Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study. Clin Infect Dis 1995; 20:1195-1200
  45. Jackson MA, Burry VF, Olson LC, et al. Breakthrough sepsis in macrolide-resistant pneumococcal infection. Pediatr Infect Dis J 1996; 15:1049-1051
  46. Rodvold KA, Gotfried MH, Danziger LH, et al. Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers. Antimicrob Agents Chemother 1997; 41:1399-1402
  47. Genne D, Siegrist HH, Humair L, et al. Clarithromycin versus amoxicillin-clavulanic acid in the treatment of community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1997; 16:783-788
  48. Bohte R, van't Wout JW, Lobatto S, et al. Efficacy and safety of azithromycin versus benzylpenicillin or erythromycin in community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1995; 14:182-187
  49. Matsumura SO, Trpeski L, Pong-Porter S, et al. The Canadian Bacterial Surveillance Network: Cross-Canada surveillance of drug-resistant Streptococcus pneumoniae (DRSP) from 1988 to 1996. Paper presented at: 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 28-October 1, 1997; Toronto, Ontario, Canada
  50. Chen DK, McGeer A, de Azavedo JC, et al. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada: Canadian Bacterial Surveillance Network. N Engl J Med 1999; 341:233-239
  51. Wise R, Brenwald N, Gill M, et al. Streptococcus pneumoniae resistance to fluoroquinolones [letter]. Lancet 1996; 348:1660
  52. Doern GV, Brueggemann AB, Pierce G, et al. Antibiotic resistance among clinical isolates of Haemophilus influenzae in the United States in 1994 and 1995 and detection of b-lactamase-positive strains resistant to amoxicillin-clavulanate: results of a national multicenter surveillance study. Antimicrob Agents Chemother 1997; 41:292-297
  53. Tran JQ, Ballow CH, Forrest A, et al. Comparison of the abilities of grepafloxacin and clarithromycin to eradicate potential bacterial pathogens from the sputa of patients with chronic bronchitis: influence of pharmacokinetic and pharmacodynamic variables. J Antimicrob Chemother 2000; 45:9-17
  54. Doern GV, Brueggemann AB, Pierce G, et al. Prevalence of antimicrobial resistance among 723 outpatient clinical isolates of Moraxella catarrhalis in the United States in 1994 and 1995: results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996; 40:2884-2886
  55. File TM Jr, Segreti J, Dunbar L, et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997; 41:1965-1972

Copyright ©2001 American College of Chest Physicians

 
 

3300 Dundee Road • Northbrook, Illinois 60062-2348 • (847) 498-1400 • (800) 343-2227
Copyright ©1999-2008 American College of Chest Physicians. All Rights Reserved.
ACCP Privacy Policy | ACCP Web Site Terms of Use